Centre for Cognitive Neuroscience, Eli Lilly and Co., Erl Wood Manor, Windlesham GU20 6PH, UK.
Neuropharmacology. 2012 Mar;62(3):1349-58. doi: 10.1016/j.neuropharm.2011.08.005. Epub 2011 Aug 16.
The risk of developing schizophrenia has been linked to perturbations in embryonic development, but the physiological alterations that result from such insults are incompletely understood. Here, we have investigated aspects of hippocampal physiology in a proposed neurodevelopmental model of schizophrenia, induced during gestation in rats by injection of the antimitotic agent methylazoxymethanol acetate (MAM) at embryonic day 17 (MAM(E17)). We observed a reduction in synaptic innervation and synaptic transmission in the dorsal hippocampus of MAM(E17) treated rats, accompanied by a pronounced increase in CA1 pyramidal neuron excitability. Pharmacological investigations suggested that a deficit in GABAergic inhibition could account for the increase in excitability; furthermore, some aspects of the hyper-excitability could be normalised by the GABA(A) receptor (GABA(A)R) potentiator diazepam. Despite these alterations, two major forms of synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD) could be readily induced. In contrast, there was a substantial deficit in the reversal of LTP, depotentiation. These findings suggest that delivering neurodevelopmental insults at E17 may offer insights into some of the physiological alterations that underlie behavioural and cognitive symptoms observed in schizophrenia.
精神分裂症的发病风险与胚胎发育过程中的干扰有关，但由此类损伤引起的生理变化仍不完全清楚。在这里，我们在一个假设的精神分裂症神经发育模型中研究了海马体生理学的各个方面，该模型是通过在胚胎第 17 天（MAM（E17））向大鼠注射抗有丝分裂剂甲基偶氮甲醇乙酸盐（MAM）来诱导的。我们观察到 MAM（E17）处理的大鼠背侧海马体的突触神经支配和突触传递减少，同时 CA1 锥体神经元兴奋性明显增加。药理学研究表明，GABA 能抑制的缺陷可以解释兴奋性的增加；此外，通过 GABA(A) 受体（GABA(A)R）激动剂地西泮可以使部分超兴奋性正常化。尽管存在这些改变，但两种主要形式的突触可塑性，长时程增强（LTP）和长时程抑制（LTD）可以很容易地诱导。相比之下，LTP 的反转，去极化明显不足。这些发现表明，在 E17 时进行神经发育损伤可能为理解精神分裂症中观察到的行为和认知症状的一些生理变化提供了线索。
